Effects of hyperinsulinemia on lipoprotein lipase, angiopoietin-like protein 4, and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 in subjects with and without type 2 diabetes mellitus.
Our aims were to compare the systemic effects of insulin on lipoprotein lipase (LPL) in tissues from subjects with different degrees of insulin sensitivity. The effects of insulin on LPL during a 4-hour hyperinsulinemic, euglycemic clamp were studied in skeletal muscle, adipose tissue, and postheparin plasma from young healthy subjects (YS), older subjects with type 2 diabetes mellitus (DS), and older control subjects (CS). In addition, we studied the effects of insulin on the expression of 2 recently recognized candidate genes for control of LPL activity: angiopoietin-like protein 4 (ANGPTL4) and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1. As an effect of insulin, LPL activity decreased by 20% to 25% in postheparin plasma and increased by 20% to 30% in adipose tissue in all groups. In YS, the levels of ANGPTL4 messenger RNA in adipose tissue decreased 3-fold during the clamp. In contrast, there was no significant change in DS or CS. Regression analysis showed that the ability of insulin to reduce the expression of ANGPTL4 was positively correlated with M-values and inversely correlated with factors linked to the metabolic syndrome. Expression of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 tended to be higher in YS than in DS or CS, but the expression was not affected by insulin in any of the groups. Our data imply that the insulin-mediated regulation of LPL is not directly linked to the control of glucose turnover by insulin or to ANGPTL4 expression in adipose tissue or plasma. Interestingly, the response of ANGPTL4 expression in adipose tissue to insulin was severely blunted in both DS and CS.


Insulin responsiveness of protein metabolism in vivo following bedrest in humans.
To test the influence of bedrest on insulin regulation of leucine metabolism, six normal young men were subjected to a five-step hyperinsulinemic euglycemic clamp before and after 7 days of strict bedrest. A primed-constant infusion of [1-13C]leucine at 0.12 +/- 0.02 mumol.kg-1.min-1 was used. Before bedrest, the basal rate of appearance (Ra) of intracellular leucine and leucine oxidation were 2.79 +/- 0.17 and 0.613 +/- 0.070 mumol.kg-1.min-1, respectively. Insulin caused a dose-dependent reduction of the intracellular leucine Ra and leucine oxidation to a minimum of 1.64 +/- 0.08 and 0.322 +/- 0.039 mumol.kg-1.min-1, respectively, in nonbedrested subjects (P less than 0.001). Insulin also caused a dose-dependent reduction of plasma leucine concentration from 95 +/- 4 to 38 +/- 2 mumol/l (P less than 0.001). After bedrest, subjects exhibited decreased glucose tolerance and increased endogenous insulin secretion, but basal and insulin-suppressed intracellular leucine Ra and leucine oxidation rates were not different from control. Magnetic resonance imaging of the back and lower extremities revealed a 1-4% decrease in muscle volume and a 2-5% increase in fat volume secondary to bedrest. Bedrest also resulted in a negative nitrogen balance as compared with the control period, with an average cumulative loss of 6.3 g of nitrogen after 6 days. Urinary 3-methyl-L-histidine excretion was unchanged by bed rest. Thus because negative nitrogen balance and skeletal muscle atrophy occurred in six rested subjects in the absence of changes in the two indices of protein breakdown used in this study (3-methyl-L-histidine release and leucine release), it seems likely that muscle protein synthesis was inhibited.


Effects of chytrid fungus and a glyphosate-based herbicide on survival and growth of wood frogs (Lithobates sylvaticus).
Anthropogenic-derived stressors in the environment, such as contaminants, are increasingly considered important cofactors that may decrease the immune response of amphibians to pathogens. Few studies, however, have integrated amphibian disease and contaminants to test this multiple-stressor hypothesis for amphibian declines. We examined whether exposure to sublethal concentrations of a glyphosate-based herbicide and two strains of the pathogenic chytrid fungus, Batrachochrytrium dendrobatidis (Bd) could: (1) sublethally affect wood frogs (Lithobates sylvaticus) by altering the time to and size at metamorphosis, and (2) directly affect survivability of wood frogs after metamorphosis. Neither Bd strain nor herbicide exposure alone significantly altered growth or time to metamorphosis. The two Bd strains did not differ in their pathogenicity, and both caused mortality in post-metamorphic wood frogs. There was no evidence of an interaction between treatments, indicating a lack of herbicide-induced susceptibility to Bd. However, the trends in our data suggest that exposure of wood frogs to a high concentration of glyphosate-based herbicide may reduce Bd-caused mortality compared to animals exposed to Bd alone. These results exemplify the complexities inherent when populations are coping with multiple stressors. In this case, the perceived stressor, glyphosate-based herbicide, appeared to affect the pathogen more than the host's immune system, relieving the host from disease-caused effects. This suggests caution when invoking multiple stressors as a cause for increased disease susceptibility and indicates that the effects of multiple stressors on disease outcome depend on the interrelationships of stressors to both the pathogen and the host.


The effect of amifostine on submandibular gland histology after radiation.
Background. The purpose of this study was to assess the effects of amifostine on submandibular gland histology in patients receiving chemoradiation therapy. Methods. We conducted a retrospective submandibular gland histologic slide review of HNSCC patients receiving chemoradiation for head and neck squamous cell carcinoma with three different levels of amifostine exposure. We used six scoring parameters: fatty replacement, lobular architecture degeneration, interstitial fibrosis, ductal degeneration, acinar degeneration, and inflammatory component presence. Results. Differences in gender, tumor stage, amifostine dose, age, number of days after neck dissection, and smoking history (pack years) exposure were not significant between the three groups, although there was a difference between groups in the primary subsite (P = 0.006). The nonparametric Cuzick's test for histologic parameters with varied amifostine treatment showed no significance among the three groups. Conclusions. Although patients did not receive a full dose of amifostine due to side effects, varying doses of amifostine had no apparent evident cytoprotective effects in three groups of cancer patients treated with primary chemoradiation.


Skull ecomorphological variation of narwhals (Monodon monoceros, Linnaeus 1758) and belugas (Delphinapterus leucas, Pallas 1776) reveals phenotype of their hybrids.
Narwhals and belugas are toothed whales belonging to the Monodontidae. Belugas have a circumpolar Arctic and sub-Artic distribution while narwhals are restricted to the Atlantic Arctic. Their geographical ranges overlap during winter migrations in the Baffin Bay area (Canada/West Greenland) and successful interbreeding may occur. Here, we employed geometric morphometrics on museum specimens to explore the cranium and mandible morphology of a known hybrid (NHMD MCE 1356) and the cranium morphology of a putative hybrid (NHMD 1918.104.22.168) relative to skull morphological variation in the parental species. Specifically, we used 3D models of skulls from 69 belugas, 86 narwhals, and the two known/putative hybrids and 2D left hemi-mandibles from 20 belugas, 64 narwhals and the known hybrid. Skull shape analyses allowed clear discrimination between species. Narwhals are characterised by a relatively short rostrum and wide neurocranium while belugas show a more elongated and narrower cranium. Sexual size dimorphism was detected in narwhals, with males larger than females, but no sexual shape dimorphism was detected in either species (excluding presence/absence of tusks in narwhals). Morphological skull variation was also dependent on different allometric slopes between species and sexes in narwhals. Our analyses showed that the cranium of the known hybrid was phenotypically close to belugas but its 2D hemi-mandible had a narwhal shape and size morphology. Both cranium and mandible were strongly correlated, with the pattern of covariation being similar to belugas. The putative hybrid was a pure male narwhal with extruded teeth. Comparison of genomic DNA supported this result, and stable carbon and nitrogen isotope values suggested that the putative hybrid had a more benthic foraging strategy compared to narwhals. This work demonstrates that although the known hybrid could be discriminated from narwhals and belugas, detection of its affinities with these parental species was dependent on the part of the skull analysed.


Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy.
Multiple biological barriers must be considered in the design of nanomedicines, including prolonged blood circulation, efficient accumulation at the target site, effective penetration into the target tissue, selective uptake of the nanoparticles into target cells, and successful endosomal escape. However, different particle sizes, surface chemistries, and sometimes shapes are required to achieve the desired transport properties at each step of the delivery process. In response, this review highlights recent developments in the design of switchable nanoparticles whose size, surface chemistry, shape, or a combination thereof can be altered as a function of time, a disease-specific microenvironment, and/or via an externally applied stimulus to enable improved optimization of nanoparticle properties in each step of the delivery process. The practical use of such nanoparticles in chemotherapy, bioimaging, photothermal therapy, and other applications is also discussed.


TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist.
Fibrocytes (FC) are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO). FCs express high levels of thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R). These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH) or M22 (activating antibody to TSHR) induces the production of numerous cytokines, including tumor necrosis factor α (TNFα). Teprotumumab (TMB) is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs. To characterize the molecular mechanisms underlying TSH-induced TNFα production by FCs, and the role of IGF-1R blockade by TMB. FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-κB and Akt, respectively), and TMB. TNFα protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR. Treatment with TSH/M22 induced TNFα protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001). TMB decreased TSH-induced TNFα protein production in circulating FCs from mean fluorescent index (MFI) value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001). TMB also decreased M22-induced TNFα protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001). TSH/M22 stimulates FC production of TNFα mRNA and protein. This process involves the transcription factor NF-κB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFα production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFα production, TMB may be a promising therapeutic agent for GO.


All that glitters is not gold.
Solitary pulmonary nodules (SPN) are a diagnostic dilemma with a long list of differential diagnosis which extends to include both horizons i.e., benign as well as malignant conditions. Fortunately, there are some factors which favour benign over malignant; one such factor is presence of fat.1 We present here a case of a 40 years old male who underwent x-ray due to haemoptysis and cough which demonstrated a coin lesion; subsequently, PET-CT scan was requested for characterization of the lesion and concurrent staging which revealed mildly avid fat containing lesion in right lung diagnostic of pulmonary hamartoma.


LongAxis: A MATLAB-based program for 3D quantitative analysis of epithelial cell shape and orientation.
Epithelial morphogenesis, a fundamental aspect of development, generates 3-dimensional tissue structures crucial for organ function. Underlying morphogenetic mechanisms are, in many cases, poorly understood, but mutations that perturb organ development can affect epithelial cell shape and orientation - difficult features to quantify in three dimensions. The basic structure of the eye is established via epithelial morphogenesis: in the embryonic optic cup, the retinal progenitor epithelium enwraps the lens. We previously found that loss of the extracellular matrix protein laminin-alpha1 (lama1) led to mislocalization of apical polarity markers and apparent misorientation of retinal progenitors. We sought to visualize and quantify this phenotype, and determine whether loss of the apical polarity determinant pard3 might rescue the phenotype. To this end, we developed LongAxis, a MATLAB-based program optimized for the retinal progenitor neuroepithelium. LongAxis facilitates 3-dimensional cell segmentation, visualization, and quantification of cell orientation and morphology. Using LongAxis, we find that retinal progenitors in the lama1-/- optic cup are misoriented and slightly less elongated. In the lama1;MZpard3 double mutant, cells are still misoriented, but larger. Therefore, loss of pard3 does not rescue loss of lama1, and in fact uncovers a novel cell size phenotype. LongAxis enables population-level visualization and quantification of retinal progenitor cell orientation and morphology. These results underscore the importance of visualizing and quantifying cell orientation and shape in three dimensions within the retina.


Two new aurones from marine brown alga Spatoglossum variabile.
Two new aurones, 4'-chloro-2-hydroxyaurone (1) and 4'-chloroaurone (2) were isolated from Spatoglossum variabile. The structures of these compounds were elucidated by modern spectroscopic techniques.


Pretreatment prognostic factors in colorectal cancer patients with synchronous liver metastases.
Potential pretreatment prognostic variables for patients presenting with liver metastases at the time of resection of primary colorectal cancers were evaluated in 42 consecutive patients resected over two years. Survival was bimodal with 12 patients dead within 6 months of surgery and the remaining patients dead or alive at follow-up at 6 to 27 months (median 9 months). Preoperative peripheral lymphocytes (P = 0.0008), alkaline phosphatase (P = 0.0056), and serum glutamic oxaloacetic and pyruvic transaminases (SGOT, P = 0.0048, and SGPT, P = 0.0031) were significant prognostic factors. The transaminases were prognostic within the normal ranges for the hospital laboratory. Age, sex, hematocrit, platelet count, bilirubin, cholesterol, albumin, protein, creatinine, tumor differentiation, bowel penetration, nodal involvement, operative blood loss, transfusions and chemotherapy were not related to survival. These results indicate that normal liver function tests in patients with colorectal liver metastases have significant prognostic value. Immune function as reflected by lymphocyte count may also play a role in these patients' survivals.


Synthesis of novel analogues of 1alpha,25-dihydroxyvitamin D(3) with side chains at C-18.
Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).


[Somatosensory evoked potentials and the spinal cord conduction velocity in multiple sclerosis].
Somatosensory evoked potentials (SSEP) on n. medianus and n. tibialis stimulation were studied in 25 patients with multiple sclerosis (MS) and 30 normals (N). Sensory conduction velocity (SVC) calculated by indirect method using formula of Eisen and Nudelman (1979) in which instead of time parameters of F- and M-responses latencies of the N13 and N21 for hand and leg, respectively, of spinal SSEP was used. Normal spinal cord SCV was 60.8 +/- 1.3 m/s, SCV in MS was 51.9 +/- 10.7 m/s. Extreme dispersion of data in MS is caused by false "normal and paradoxically "increased" SCV values in patients. The causes of false results are analysed. In difference of Eisen and Nudelman methods, the proposed approach allows proper clinical interpretation of the false values and excludes possibility of diagnostic mistakes, as in each case the whole set of the data from cerebral and spinal SSEP is interpreted systematically.


Where do poor women in developing countries give birth? A multi-country analysis of demographic and health survey data.
In 2008, over 300,000 women died during pregnancy or childbirth, mostly in poor countries. While there are proven interventions to make childbirth safer, there is uncertainty about the best way to deliver these at large scale. In particular, there is currently a debate about whether maternal deaths are more likely to be prevented by delivering effective interventions through scaled up facilities or via community-based services. To inform this debate, we examined delivery location and attendance and the reasons women report for giving birth at home. We conducted a secondary analysis of maternal delivery data from Demographic and Health Surveys in 48 developing countries from 2003 to the present. We stratified reported delivery locations by wealth quintile for each country and created weighted regional summaries. For sub-Saharan Africa (SSA), where death rates are highest, we conducted a subsample analysis of motivations for giving birth at home. In SSA, South Asia, and Southeast Asia, more than 70% of all births in the lowest two wealth quintiles occurred at home. In SSA, 54.1% of the richest women reported using public facilities compared with only 17.7% of the poorest women. Among home births in SSA, 56% in the poorest quintile were unattended while 41% were attended by a traditional birth attendant (TBA); 40% in the wealthiest quintile were unattended, while 33% were attended by a TBA. Seven per cent of the poorest women reported cost as a reason for not delivering in a facility, while 27% reported lack of access as a reason. The most common reason given by both the poorest and richest women for not delivering in a facility was that it was deemed "not necessary" by a household decision maker. Among the poorest women, "not necessary" was given as a reason by 68% of women whose births were unattended and by 66% of women whose births were attended. In developing countries, most poor women deliver at home. This suggests that, at least in the near term, efforts to reduce maternal deaths should prioritize community-based interventions aimed at making home births safer.


[Cancellation of scheduled surgery at a university hospital: an exploratory study].
In spite of the extensive available literature on surgery patients' preparation and on the performance of surgeries, the focus given to the cancellation of the surgical act has been quite restricted. This study aims at identifying the number of scheduled and cancelled surgeries as well as the services that are mostly affected by such cancellations and was carried out in the surgery service of a big public university hospital located in the metropolitan area of Fortaleza, Ceará. The data were collected through surgery registration books, daily maps of surgery schedules and from the files of patients scheduled for surgery from September to December, 1996. The gathered data were analyzed quantitatively and introduced in charts. The results demonstrate that from the 1,145 surgeries programmed in the selected period, 379 (33%) had been cancelled. The mostly prejudiced services were General Surgery, Ophthalmology, Head and Neck Surgery, Trauma and Orthopedics, Otorhinolaryngology, Nephrology and Renal Transplant, and Proctology. Further investigation in this area in order to know the determinant causes of surgery cancellation as well as the participation of nursing in the study of this problem are necessary.


[Differential diagnosis of medial neck tumors. 2 cases of thyroid malignancy].
Mobile swellings in the neck are a frequent finding in Ear Nose and Throat practice. Any such swelling demands a thorough investigation since there are many possible causes. In doubtful cases, histological examination is necessary. Two cases are presented in which small mobile nodes in the mid-line of the neck, anterior to the larynx, were the presenting symptom of a thyroid carcinoma. The laboratory findings and thyroid scan were normal in these two patients.


Predicting attachment in Portuguese infants born very or extremely preterm: Understanding the roles of infant regulatory behavior, maternal sensitivity, and risk factors.
A growing body of research shows that early attachment relationships are foundational for children's later developmental and psychosocial outcomes. However, findings are mixed regarding whether preterm birth predicts later attachment, but insecurity is generally more prevalent among infants at higher medical and/or social/familial risk. This longitudinal study aimed to identify specific relational, familial/demographic, and perinatal predictors of attachment in a sample of 63 Portuguese infants born very or extremely preterm (VEPT, <32 gestational weeks) and their mothers from diverse socioeconomic backgrounds. One-third of the mothers had social/family risk factors (e.g., single parent, immigrant, unemployed, low education, and/or low income). At 3 months (corrected age), dyads were observed during social interaction in the Face-to-Face Still-Face paradigm (FFSF) and during free play. At 12 months, mother-infant dyads were observed in Ainsworth's Strange Situation. Over half (58.7%) of the infants were classified as insecurely attached. Social-Positive Oriented regulatory behavior pattern, higher maternal sensitivity, higher infant cooperation during free play, number of siblings and an absence of social/family risk factors were associated with attachment security. Perinatal variables were unrelated to attachment. Findings indicate that both relational and social contextual factors contribute to attachment in this biologically vulnerable sample.


The effect of a high partial pressure of carbon dioxide environment on metabolism and immune functions of human peritoneal cells-relevance to carbon dioxide pneumoperitoneum.
Our purpose was to evaluate in vitro the effect of a high partial pressure of carbon dioxide environment used in laparoscopy on metabolic and immune response of various human peritoneal cells. Polymorphonuclear leukocytes were obtained from 5 healthy volunteers, peritoneal macrophages were obtained from the effluent of 8 patients undergoing continuous ambulatory peritoneal dialysis, and human peritoneal mesothelial cell cultures were prepared from omentum derived from 5 patients undergoing elective surgery. The cells were exposed to a laparoscopy-like environment (1 atmosphere carbon dioxide and 0.2 atmosphere oxygen), to a control gas mixture (1 atmosphere helium and 0.2 atmosphere oxygen), or air for 3 hours. After exposure to gas mixtures, cell functions were tested at various recovery periods. Three hours of exposure to a high partial pressure of carbon dioxide had no effect on viability of peritoneal macrophages and human peritoneal mesothelial cells, tested by trypan blue dye uptake and lactate dehydrogenase release. A high partial pressure of carbon dioxide decreased the mitochondrial dehydrogenases activity of peritoneal macrophages and human peritoneal macrophage cells by 60%, assayed by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction. High partial pressure of carbon dioxide blocked the superoxide release from activated polymorphonuclear leukocytes and the secretion of interleukin 1beta from stimulated peritoneal macrophages, and human peritoneal macrophage cells were decreased by 15% and 30% and the secretion of tumor necrosis factor-alpha from peritoneal macrophages was suppressed by 85%. Mitochondrial activity, polymorphonuclear leukocyte function, and interleukin 1beta and tumor necrosis factor-alpha secretion returned to normal after a recovery period of 12 to 24 hours, 4.5 hours, and 24 hours, respectively. In the control experiments exposure of cells to helium had no suppressive effect. Exposure of cells to a high partial pressure of carbon dioxide environment suppresses the inflammatory and metabolic responses of peritoneal cells. We suggest that this suppressive effect may contribute to the low postsurgery adhesion formation and the reduction in postoperative pain observed in laparoscopy. Nevertheless, the suppression of the immune response should also be taken into account for operations involving a high risk of bacterial dissemination.


One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability.
Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin-derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline-amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability.


Rapid detection of Mycobacterium tuberculosis using recombinase polymerase amplification: A pilot study.
Tuberculosis remains one of the leading causes of death worldwide, especially in low- and middle-income countries. Tuberculosis treatment and control efforts are hindered by the difficulty in making the diagnosis, as currently available diagnostic tests are too slow, too expensive, or not sufficiently sensitive. Recombinase polymerase amplification (RPA) is a novel technique that allows for the amplification of DNA rapidly, at constant temperature, and with minimal expense. We calculated and compared the limit of detection, sensitivity, and specificity of two RPA-based assays for the diagnosis of pulmonary tuberculosis, using two sets of published primers. We also calculated and compared the assays' limits of detection and compared their performance using two different DNA extraction methods prior to amplification (a commercially available DNA extraction kit vs. the chelex method). The RPA-lateral flow assay had a limit of detection of 5 fg/μL of DNA, a sensitivity of 53.2%, and a specificity of 93.3%, while the real time-RPA assay had a limit of detection of 25 fg/μL of DNA, a sensitivity of 85.1%, and a specificity of 93.3%. There was no difference in assay performance when DNA extraction was carried out using the commercial kit vs. the chelex method. The real-time RPA assay has adequate sensitivity and specificity for the diagnosis of pulmonary tuberculosis and could be a viable diagnostic tool in resource-limited settings, but the lateral flow assay did not perform as well, perhaps due to the fact we used stored sputum specimens from a biorepository. More work is needed to optimize the RPA-lateral flow assay, to get a more accurate estimate of its specificity and sensitivity using prospectively collected specimens, and to develop both assays into point-of-care tests that can be easily deployed in the field.


Obligate necrophagy in a social bee.
The social bee Trigona hypogea uses carrion instead of pollen as a protein source. Nests lack stored pollen, pollen is absent in larval provisions, and corbiculae for pollen transport on worker hind legs are reduced. Glandular secretions of 20 percent protein content appear to replace stored pollen. Toothed mandibles, pheromonal recruitment to resources, and aggressive foraging behavior facilitated evolution of necrophagy in this tropical forest bee lineage.


Improvements in cognitive function and quantitative sleep electroencephalogram in obstructive sleep apnea after six months of continuous positive airway pressure treatment.
Untreated obstructive sleep apnea (OSA) is associated with cognitive deficits and altered brain electrophysiology. We evaluated the effect of continuous positive airway pressure (CPAP) treatment on quantitative sleep electroencephalogram (EEG) measures and cognitive function. We studied 167 patients with OSA (age 50 ± 13, AHI 35.0 ± 26.8) before and after 6 months of CPAP. Cognitive tests assessed working memory, sustained attention, visuospatial scanning, and executive function. All participants underwent overnight polysomnography at baseline and after CPAP. Power spectral analysis was performed on EEG data (C3-M2) in a sub-set of 90 participants. Relative delta EEG power and sigma power in NREM and EEG slowing in REM were calculated. Spindle densities (events/min) in N2 were also derived using automated spindle event detection. All outcomes were analysed as change from baseline. Cognitive function across all cognitive domains improved after six months of CPAP. In our sub-set, increased relative delta power (p < .0001) and reduced sigma power (p = .001) during NREM were observed after the 6-month treatment period. Overall, fast and slow sleep spindle densities during N2 were increased after treatment. Cognitive performance was improved and sleep EEG features were enhanced when assessing the effects of CPAP. These findings suggest the reversibility of cognitive deficits and altered brain electrophysiology observed in untreated OSA following six months of treatment.


Synthesis and antimicrobial activity of 8-alkylberberine derivatives with a long aliphatic chain.
The compounds 8-ethyl- (2), 8-butyl- (3), 8-hexyl- (4), 8-octyl- (5), 8-decyl- (6) and 8-dodecylberberine chloride (7) were synthesized and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Substitution of the alkyl groups at C-8 led to significant changes in the antimicrobial activity. All compounds were more potent against the tested microorganisms than berberine (1), especially against Gram-positive bacteria. The antimicrobial activity increased as the length of aliphatic chain was elongated and then decreased gradually when the alkyl chain exceeded eight carbon atoms. 8-octylberberine (5) displayed the highest antimicrobial activity of all compounds. The toxicity of compounds 2 - 7 was stronger than that of 1. However, upon elongating the aliphatic chain, the toxicity decreased gradually.


[Personality characteristics, defence mechanisms and binge eating in obese patients].
This study aimed to investigate defence mechanisms and personality characteristics in obese subjects. In particular, we compared the use of defence mechanisms in two groups: obese persons vs. normal weight subjects. We also compared the defence mechanisms and personality characteristics of two groups of obese subjects: those with Binge Eating Disorder vs. those without this disorder. Finally, we investigated the presence of possible differences linked to gender or to age of onset of obesity. 93 obese subjects and 68 normal weight subjects were administered a test battery composed of the following self-complete questionnaires (in the Italian version): Binge Eating Scale, Response Evaluation Measure-71, Eating Disorder Inventory-2 and Minnesota Multiphasic Personality Inventory). Obese subjects appear to use specific defence mechanisms. A gender effect was found on the use of defence mechanisms, on the psychological characteristics associated to an Eating Disorder and on personality features. Obese subjects with Binge Eating Disorder showed a marked tendency to manifest anxiety and bulimic behaviour. Obesity with onset in adolescence was associated with the possibility of developing drug dependence. Specific defence characteristics and personality features in obese subjects should be taken into account in designing a slimming program.


Probable lumbar acute non-compressive nucleus pulposus extrusion in a cat with acute onset paraparesis.
A spinal cord lesion localised caudal to the L6 spinal segment was diagnosed in a 2-year-old female spayed domestic longhair cat with acute onset paraparesis. Magnetic resonance imaging findings were consistent with an acute, non-compressive nucleus pulposus extrusion of the L5-L6 intervertebral disc. The cat was successfully managed with supportive care, including cage confinement.


Refinement of Swedish administrative registers to monitor stroke events on the national level.
Routinely collected databases are kept for administrative purposes. We have refined the analyses of the Swedish National Patient Register and the Cause of Death Register and explored their validity to monitor stroke at the population level. First-ever strokes (incident cases) and all stroke events were measured by combining the two administrative registers and adding refinements. The administrative registers were validated against the Northern Sweden MONICA, a well-validated population-based epidemiological stroke register. Positive predictive values (PPVs) and sensitivity were calculated. After refinements (restriction to first-ever strokes and additional minor delineations), the PPV of the two administrative registers combined was 94% and sensitivity 92% when compared with all MONICA stroke categories together. For stroke attacks (first and recurrent events together), the PPV in the administrative registers was 85% and sensitivity 91%. The PPV was higher in women than in men, whereas the sensitivity was similar. The PPV was lower but sensitivity higher in people below compared with those above 75 years of age. Both PPV and sensitivity were lower among fatal cases than among cases that survived 28 days. After refinement, Swedish national administrative registers may, with some caveats, be used as a low-resource-consuming alternative to crudely monitor stroke incidence rates at the national level. If further accuracy is strived for, high-quality conventional epidemiological registers are required.


The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis.
The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.


Modification by WR 2721 of the response to chemotherapy of tumours and normal tissues in the mouse.
The sulphydryl compound WR 2721 has been combined with a range of cytotoxic drugs in the mouse and the effects upon tumours and normal tissues determined. In the acute lethality (LD50/30) assay, mean protection factors produced by WR 2721 (200 or 400 mg kg-1) were generally less than 1.3 for cyclophosphamide (CTX), CCNU and chlorambucil (CHL) but a protection factor of 1.7 was obtained for cisplatinum (cis-P) in combination with 400 mg kg-1 of WR 2721. No protection against the depression of peripheral white cell count seen at 3 days after CTX, CCNU or cis-P was obtained with either 200 or 400 mg kg-1 of WR 2721. Significant protection of the RIF-1 sarcoma by WR 2721 against CTX and cis-P induced growth delay was seen. In the KHT sarcoma, WR 2721 produced small reductions in the growth delay caused by CCNU, melphalan and CHL but these were not statistically significant. These data show less differential normal tissue protection by WR 2721 than do a number of reports in the literature.


[Summary of the Dutch College of General Practitioners' practice guideline on food hypersensitivity].
October 2010 the Dutch College of General Practitioners issued a revised version of their previous practice guideline of 1995 on food hypersensitivity in infants. If patients suspect either themselves or their child of having a food allergy, this is usually not demonstrated in subsequent investigation. Wrongly prescribed elimination diets may have adverse effects. Examination of serum specific IgE levels has no place in the diagnosis of food allergy in general practice. An open elimination challenge is especially suitable in order to exclude a food allergy. A sure diagnosis of food allergy can only be made by a double-blind placebo-controlled food challenge. There are no proven effective measures that can prevent food allergy.


[Tumour staged surgery of endolymphatic sac tumors (ELST)].
Endolymphatic sac tumours (ELST) have only been known as own tumour entities since 1984. ELST might occur solitarily and sporadically as well as hereditary connected to von Hippel-Lindau disease (VHL). This connection has been observed in 1992 for the first time and confirmed by molecular genetic analyses of the VHL gen. There is no agreement yet concerning diagnostics and therapy. Our attempt of classifying this type of tumour is the first one. According to our own experience and to literature, we suggest the following classification: ELST type A is locally confined without erosions of the temporal bone nor infiltration of the subarachnoidal area; ELST type B with bony infiltration of the labyrinth block and clinical hearing loss, and ELST type C with additional infiltration of the sigmoid sinus and the vein of jugular bulb. Preoperative diagnostics are performed according to defined radiological criteria in CT and MRI scans including MR-angiography. In 6 patients, including two with a VHL syndrome, ELST was completely sanitized by stage-compatible surgery, using translabyrintine to infratemporal approaches, according to the tumour classification that we developed. The VII (th) nerve could be saved in all tumour stages, and in stage ELST type A the VIII (th) nerve as well. All patients remained without local recurrence in MRI check during the observation period of 4 to 38 months. Our stage-compatible surgery of ELST allows total tumor removal with minor morbidity. In contrast to the antero-, retrosigmoidal and suboccipital approaches, the tumour matrix can be safely removed via transmastoidal approach to exclude local recurrences.


Implicit sequence learning in deaf children with cochlear implants.
Deaf children with cochlear implants (CIs) represent an intriguing opportunity to study neurocognitive plasticity and reorganization when sound is introduced following a period of auditory deprivation early in development. Although it is common to consider deafness as affecting hearing alone, it may be the case that auditory deprivation leads to more global changes in neurocognitive function. In this paper, we investigate implicit sequence learning abilities in deaf children with CIs using a novel task that measured learning through improvement to immediate serial recall for statistically consistent visual sequences. The results demonstrated two key findings. First, the deaf children with CIs showed disturbances in their visual sequence learning abilities relative to the typically developing normal-hearing children. Second, sequence learning was significantly correlated with a standardized measure of language outcome in the CI children. These findings suggest that a period of auditory deprivation has secondary effects related to general sequencing deficits, and that disturbances in sequence learning may at least partially explain why some deaf children still struggle with language following cochlear implantation.


Long-term effects of prenatal stress: changes in adult cardiovascular regulation and sensitivity to stress.
Prenatal environment exerts profound influences on the development of an organism and stressful events during pregnancy can bring about long-term physiological/behavioral alterations in the offspring. Epidemiological evidence points to a relationship between intrauterine growth restriction (IUGR), body weight at birth, and adult cardiovascular disease. Experimental research employed different models of IUGR, including altered maternal nutrition, exposure to elevated glucocorticoids, and reduced placental perfusion, all of which can program, when acting during sensitive temporal windows of foetal life, alterations in cardiovascular regulation and stress sensitivity. Original data are presented indicating that prenatal psychological stress (intermittent restraint) does not induce in the rat adult offspring changes of plasma corticosterone levels, cardiac autonomic modulation, and circadian rhythmicity of heart rate (HR), body temperature (T) and physical activity (Act) at rest. However, prenatally stressed rats--when further stimulated in adulthood--exhibit prolonged adrenocortical stress responsivity, disturbed circadian rhythmicity of HR, T, and Act, and increased adrenal weight. This evidence supports the idea that prenatal stress per se does not change dramatically a given structure or function, but it affects resilience and renders the animal more susceptible to pathophysiological outcomes when further insults occur during adulthood.


Implementation of Resonance Tracking for Assuring Reliability in Resonance Enhanced Photothermal Infrared Spectroscopy and Imaging.
Photothermal-induced resonance (PTIR) is a method for optical spectroscopy that allows for infrared (IR) chemical imaging at spatial resolution below the limit of diffraction. By using the mechanical resonance of the cantilever for amplification the technique has been shown to allow sensitivity down to single monolayers. In this work, we discuss the challenges that must be overcome for performing stable resonant PTIR measurements and how imprecise experimental procedures can lead to irreproducible or even erroneous results. We also present a controller design that continuously readjusts the excitation frequency of a PTIR setup back to the resonance frequency in order to allow for accurate resonance-enhanced PTIR measurements. This controller can be used together with a broad range of atomic force microscopes. Schematics and program code for the controller are made freely available.


Barriers and enablers to implementing an induction of labour guideline: A clinician survey.
Clinical guidelines improve outcomes, but poor compliance with recommendations is common. Insight into perceived barriers and enablers to the implementation of guidelines can engage maternity care providers and inform strategies for effective implementation. To identify the perceived barriers and enablers to implementing the 2020 'Induction of Labour [IOL] in Aotearoa New Zealand; a Clinical Practice Guideline.' Electronic anonymous survey of clinical leaders in midwifery, obstetrics, and neonatology in New Zealand, from August to November 2021. Recruitment of participants was initially through provided lists of national clinical leads, followed by chain sampling. There were 32 of 89 surveys returned (36%). The most frequently identified enablers were implementation tools such as 'standardised IOL request form' and 'peer review process,' and administrative support and dedicated time. Six maternity hospitals already had peer review in place, whereby IOL requests that did not adhere to guidelines were reviewed by a multidisciplinary group of senior colleagues or peers, with individual feedback to the referring clinician. Attitudes in the form of 'existing systems, routines and culture' was the most frequently identified barrier, followed by external barriers such as 'lack of human resources.' Overall, few barriers were identified to implementing this guideline, and some of the key enablers were already in place. The identified enablers warrant future research to develop and evaluate effectiveness in improving outcomes.


Handwritten Digit Recognition Using K Nearest-Neighbor, Radial-Basis Function, and Backpropagation Neural Networks.
Results of recent research suggest that carefully designed multilayer neural networks with local "receptive fields" and shared weights may be unique in providing low error rates on handwritten digit recognition tasks. This study, however, demonstrates that these networks, radial basis function (RBF) networks, and k nearest-neighbor (kNN) classifiers, all provide similar low error rates on a large handwritten digit database. The backpropagation network is overall superior in memory usage and classification time but can provide "false positive" classifications when the input is not a digit. The backpropagation network also has the longest training time. The RBF classifier requires more memory and more classification time, but less training time. When high accuracy is warranted, the RBF classifier can generate a more effective confidence judgment for rejecting ambiguous inputs. The simple kNN classifier can also perform handwritten digit recognition, but requires a prohibitively large amount of memory and is much slower at classification. Nevertheless, the simplicity of the algorithm and fast training characteristics makes the kNN classifier an attractive candidate in hardware-assisted classification tasks. These results on a large, high input dimensional problem demonstrate that practical constraints including training time, memory usage, and classification time often constrain classifier selection more strongly than small differences in overall error rate.


No association between rheumatoid arthritis and cognitive impairment in a cross-sectional national sample of older U.S. adults.
Studies suggest an increased prevalence of cognitive impairment (CI) among people with rheumatoid arthritis (RA). However, most prior studies have used convenience samples which are subject to selection biases or have failed to adjust for key confounding variables. We thus examined the association between CI and RA in a large national probability sample of older US adults. Data were from interviews with 4462 participants in the 2016 wave of the nationally representative U.S. Health and Retirement Study with linked Medicare claims. RA diagnoses were identified via a minimum of two ICD-9CM or ICD-10 codes in Medicare billing records during the prior 2 years. The Langa-Weir Classification was used to classify cognitive status as normal, cognitively impaired non-dementia (CIND), or dementia based on a brief neuropsychological battery for self-respondents and informant reports for proxy respondents. We compared the odds of CI between older adults with and without RA using logistic regression, adjusted for age, education, gender, and race. Medicare records identified a 3.36% prevalence of RA (150/4462). While age, gender, education, and race independently predicted CI status, controlling for these covariates we found no difference in CI prevalence according to RA status (prevalent CI in 36.7% of older adults with RA vs. 34.0% without RA; adjusted OR = 1.08, 95% CI 0.74-1.59, p = .69). There was no association between RA and CI in this national sample of older U.S. adults.


Genetic resistance to avian pathogenic Escherichia coli (APEC): current status and opportunities.
Infections with avian pathogenic Escherichia coli (APEC) can be extremely detrimental to poultry health and production. Investigating host genetic variation could identify the biological mechanisms that control resistance to this pathogen and allow selection for improved resistance in experimental and commercial poultry populations. In this review, the current knowledge of how host genetics contributes to APEC resistance and future opportunities that would benefit the understanding or application of genetic resistance are discussed. Phenotypes, such as antibody responses, lesion scores, and mortality, revealed that genetic background impacts APEC resistance and interacts with other factors including the environment and challenge conditions. Experiments have used divergent selection for APEC-specific antibody levels to facilitate genetic studies, estimated heritabilities in relevant traits, detected quantitative trait loci using microsatellites, and made associations with sequence variation in the major histocompatibility complex, which collectively suggest that improving APEC resistance through selection is feasible, although genetic control is partial, complex, and highly polygenic. Additionally, functional genomics techniques have identified antimicrobial responses, toll-like receptor and cytokine signalling, and the cell cycle as central pathways in the host response to APEC challenge. Opportunities for future research are discussed, including the expansion of existing lines of research and the application of new technologies that are relevant to the study of host genetics and APEC. This review closes with prospective strategies for improvement of host genetic resistance to APEC.


Evidence from d+Au measurements for final-state suppression of high-p(T) hadrons in Au+Au collisions at RHIC.
We report measurements of single-particle inclusive spectra and two-particle azimuthal distributions of charged hadrons at high transverse momentum (high p(T)) in minimum bias and central d+Au collisions at sqrt[s(NN)]=200 GeV. The inclusive yield is enhanced in d+Au collisions relative to binary-scaled p+p collisions, while the two-particle azimuthal distributions are very similar to those observed in p+p collisions. These results demonstrate that the strong suppression of the inclusive yield and back-to-back correlations at high p(T) previously observed in central Au+Au collisions are due to final-state interactions with the dense medium generated in such collisions.


The fragility of statistically significant results in otolaryngology randomized trials.
The American Academy of Otolaryngology-Head and Neck Surgery regards randomized controlled trials as class A evidence. A novel method to determine the robustness of outcomes in trials is the fragility index. This index represents the number of patients whose status would have to change from a non-event to an event to make a statistically significant result non-significant. Investigators included otolaryngology journals listed in the top 10 of one or both of Google Scholar Metrics and Clarivate Analytics' Journal rankings. For inclusion, a randomized controlled trial needed to report a one-to-one random assignment of participants to condition, contain two parallel arms or have used a two-by-two factorial design, and report at least one statistically significant dichotomous outcome. Sixty-nine trials met inclusion criteria. The median fragility index was three events (interquartile range 1-7.5). Median sample size was 72 (interquartile range 50-102.5). Modest correlations were observed between fragility index and total sample size (r = 0.27) and fragility index and event rate (r = 0.46). Investigators found no correlation between fragility index and impact factor or Science Citation Index. In 39% (27/69) of trials, the number lost to follow-up was equal to or greater than the fragility index. A median fragility index of 3 indicates that three people, on average, are needed to alter the outcomes in otolaryngology trials. This indicates that the results of two-group randomized controlled trials reporting binary endpoints published in otolaryngology journals may frequently be fragile.


International prognostic scoring system for Waldenstrom macroglobulinemia.
Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 x 10(9)/L, beta2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.


Avoidance learning under hypo and hyperglycemia in rats.
Learning behaviour under different glycaemic conditions were studied in albino rats using an avoidance box. When insulin and glucose levels were low after fasting, animals showed delay in avoidance learning. But there was no change in acquisition of learning after hypoglacaemia induced by insulin. This difference in behaviour under hypoglycaemia of almost similar severity is possibly due to difference in its rate of induction and activation of counter regulatory neuro-endocrine mechanisms. Diabetic (alloxan) rats failed to improve learning. Besides, hyperglycemia, other factors like metabolic disturbances, cytotoxic effects of alloxan may have inhibited learning in this group. Hypo or hyperglycemia disturb the function of neuronal substrates responsible for learning and memory.


Iodine-induced thyroid dysfunction.
To summarize the mechanisms of iodine-induced hypothyroidism and hyperthyroidism, identify the risk factors for thyroid dysfunction following an iodine load, and summarize the major sources of excess iodine exposure. Excess iodine is generally well tolerated, but individuals with underlying thyroid disease or other risk factors may be susceptible to iodine-induced thyroid dysfunction following acute or chronic exposure. Sources of increased iodine exposure include the global public health efforts of iodine supplementation, the escalating use of iodinated contrast radiologic studies, amiodarone administration in vulnerable patients, excess seaweed consumption, and various miscellaneous sources. Iodine-induced thyroid dysfunction may be subclinical or overt. Recognition of the association between iodine excess and iodine-induced hypothyroidism or hyperthyroidism is important in the differential diagnosis of patients who present without a known cause of thyroid dysfunction.


The enigmas of the lupus anticoagulant: mechanisms, diagnosis, and management.
Lupus anticoagulant (LA) is a laboratory abnormality associated with the antiphospholipid syndrome. It is a paradoxical phenomenon in which one or more in vitro diagnostic clotting tests are prolonged and thus seem due to an anticoagulant, whereas the antiphospholipid syndrome is manifest clinically as inappropriate or excessive thrombosis. LA should be suspected when thrombosis, recurrent fetal loss, or a prolonged phospholipid (PL)-dependent clotting test is present without other identifiable causes. Despite the heterogeneity of LA antibodies, a consensus has evolved to identify the LA. Four conditions must be met for this laboratory diagnosis: 1) prolongation of a PL-based clotting test, 2) confirmation of an inhibitor-like pattern in the clotting test, 3) confirmation of PL dependence in coagulation tests, and 4) exclusion of a specific factor inhibitor. Even with an extensive armamentarium for LA diagnosis and treatment, it is still a formidable task.


Rab6 regulates recycling and retrograde trafficking of MR1 molecules.
Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important in the early response to bacterial and viral lung pathogens. MAIT cells recognize bacterial small molecule metabolites presented on the Class I-like molecule MR1. As with other Class I and Class II molecules, MR1 can likely sample ligands in the intracellular environment through multiple cellular pathways. Rab6, a small GTPase that regulates a number of endosomal trafficking pathways including retrograde transport to the trans-Golgi network (TGN), is involved in the presentation of ligands from Mycobacterium tuberculosis (Mtb) to MAIT cells. The Rab6-mediated trafficking pathway contains endosomal compartments that share features with the Mtb intracellular compartment. Using inducible expression of MR1, this study demonstrates that Rab6 regulates the recycling of MR1 molecules from the cell surface through endosomal trafficking compartments to the TGN. This Rab6-dependent pool of recycled MR1, which is available for reloading with ligands from bacterial pathogens like Mtb, may be important for early recognition of infected cells by MAIT cells in the lung.


Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes.
The aims of this study were to evaluate the safety, feasibility and tumour response of _irreversible electroporation, a non-thermal ablation technique, for the treatment of unresectable hepatocellular carcinoma. The endpoints were safety and local treatment efficacy. Patients with unresectable tumours and tumours not amenable for radiofrequency _ablation because of their vicinity to organs vulnerable to thermal damage such as the bowel or because they were close to large blood vessels that would limit efficacy of ablation due to the heat sink effect were treated with irreversible electroporation using percutaneous _ultrasound and/or computed tomography guided electrode placement between November 2008 and _December 2009. Early, late, minor and major complications were recorded. Tumour response was determined on triphasic helical computed tomography follow-up at one month, then every three months post-procedure. Eleven patients received IRE therapy to 18 HCC lesions (Mean diameter 2.44 ± 0.99 cm; range 1.0-6.1 cm) with five patients having more than one treated HCC. Mean follow-up was 18 months (range 14-24 months). Six patients required repeat treatments for local residual or recurrent disease; two of these also had IRE for distant intrahepatic recurrence. No serious complications were observed despite seven lesions lying adjacent to important structures or organs. Four patients developed transient urinary retention and seven developed transient local post-procedure pain. After IRE therapy, 13 (72%) lesions were completely ablated with 93% success for lesions ≤ 3 cm (13/14). The local recurrence-free period was 18 ± 4 months and the distance recurrence free period was 14 ± 6 months. These preliminary results suggest that IRE is a safe and feasible technique for local ablation of HCC, particularly for lesions less than 3 cm. No major complications were encountered during this study even for tumours close to essential structures or organs.


Joint effects of parasitism and pollution on oxidative stress biomarkers in yellow perch Perca flavescens.
Yellow perch Perca flavescens were collected from a contaminated site and a reference site in the St. Lawrence River, Quebec, Canada. Fish were assessed for oxidative stress (lipid peroxidation and reduced glutathione levels) and parasitism by the nematode Raphidascaris acus and metacercariae of the digenean Apophallus brevis. Lipid peroxidation is not only considered a measure of oxidative stress, but of stress in general, and thus serves as an indicator of fish health. Fish from the contaminated site exhibited higher levels of lipid peroxidation than those from the reference site, independent of parasitic infections. However, fish infected with R. acus at the contaminated site tended to have higher levels of lipid peroxidation than uninfected fish at the same site, whereas no difference was observed between infected and uninfected fish at the reference site. Yellow perch infected with > 10 metacercariae of A. brevis expressed higher levels of lipid peroxidation than those infected with < 10 metacercariae at both the contaminated and the reference sites. No differences were found in levels of reduced glutathione in liver or muscle in relation to site or either parasite species. Results support the use of lipid peroxidation as a biomarker of water contamination. They further suggest that lipid peroxidation may be used as a biomarker of pathological effects caused by parasitism. Most importantly, results demonstrate that contaminants and parasites occurring together exacerbate oxidative stress in fish, suggesting that parasitized fish in polluted environments are in a poorer state of health than uninfected fish.


Nonomuraea kuesteri sp. nov.
A Gram-positive, aerobic, non-motile actinomycete, strain GW 14-1925(T), that formed branched substrate and aerial mycelium was studied using a polyphasic approach. On the basis of 16S rRNA gene sequence similarity studies, strain GW 14-1925(T) was shown to belong to the genus Nonomuraea, being most closely related to Nonomuraea longicatena (97.9 %), Nonomuraea turkmeniaca (98.9 %), Nonomuraea helvata (98.6 %), Nonomuraea polychroma (98.5 %), Nonomuraea salmonaea (98.3 %), Nonomuraea roseoviolacea subsp. roseoviolacea (98.1 %) and Nonomuraea roseoviolacea subsp. carminata (97.7 %). The 16S rRNA gene sequence similarity to other Nonomuraea species was <97.5 %. Chemotaxonomic data [major menaquinones of the MK-9 series with minor amounts of MK-8(H(4)); major polar lipids of phospholipid type IV; fatty acids with major amounts of iso- and anteiso- and 10-methyl-branched fatty acids in combination with iso-branched 2-hydroxy fatty acids] supported allocation of the strain to the genus Nonomuraea. The results of DNA-DNA hybridizations and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain GW 14-1925(T) from closely related species; thus, GW 14-1925(T) represents a novel species of the genus Nonomuraea, for which the name Nonomuraea kuesteri sp. nov. is proposed, with GW 14-1925(T) (=DSM 44753(T)=NRRL B-24325(T)) as the type strain.


Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates, and management. A neurobehavioral review.
The non-nucleoside analog reverse transcriptase inhibitor efavirenz is one of the most common components of HAART. Neuropsychiatric symptoms are frequently reported in patients taking efavirenz-based regimens. These symptoms are usually transient, although they can sometimes persist for up to two years after initiation of treatment. This review describes in detail the most common neuropsychiatric symptoms related to efavirenz, outlines relevant and recent findings on this agent, and suggests possible interventions based on neurobehavioral results. Different recommendations on the assessment of efavirenz-related adverse events are also provided.


Intra-molecular origin of the spin-phonon coupling in slow-relaxing molecular magnets.
We perform a systematic investigation of the spin-phonon coupling leading to spin relaxation in the prototypical mononuclear single molecule magnet [(tpaPh)Fe]-. In particular we analyze in detail the nature of the most relevant vibrational modes giving rise to the relaxation. Our fully ab initio calculations, where the phonon modes are evaluated at the level of density functional theory and the spin-phonon coupling by mapping post-Hartree-Fock electronic structures onto an effective spin Hamiltonian, reveal that acoustic phonons are not active in the spin-phonon relaxation process of dilute SMMs crystals. Furthermore, we find that intra-molecular vibrational modes produce anisotropy tensor modulations orders of magnitude higher than those associated to rotations. In light of these results we are able to suggest new designing rules for spin-long-living SMMs which go beyond the tailoring of static molecular features but fully take into account dynamical features of the vibrational thermal bath evidencing those internal molecular distortions more relevant to the spin dynamics.


[Cranial MR imaging findings of carbon monoxide poisoning in asymptomatic patients in the chronic stage].
To describe MR imaging findings of the chronic stage of carbon monoxide poisoning in asymptomatic patients. Clinical data of 34 patients, who had been admitted to our hospital for carbon monoxide poisoning were reviewed and invited for control evaluation. Of the patients who accepted, ten who had no symptoms and neurological sequelae in the physical examination were included in the study. All patients had been in coma on initial admittance and had awakened after normobaric 100% oxygen therapy 1-10 years ago. Their ages were between 22-57 years (mean, 36.2 years). All patients were examined with cranial MR imaging. The most common finding was bilateral symmetric hyperintensity of the white matter more evident in the centrum semiovale with relative sparing of temporal lobes and anterior parts of frontal lobes on T2-weighted and FLAIR images in all patients. Subcortical U-fibers were intact in all patients. Cerebral cortical atrophy of variable degrees was seen in eight patients, mild atrophy of cerebellar hemispheres in seven patients, and vermian atrophy in nine patients. Corpus callosum was atrophic in two patients. Bilateral globus pallidus lesions were seen in three patients as hypointense on T1-weighted and hyperintense on T2-weighted and FLAIR images. Cerebral changes may be present in patients with severe CO poisoning even when the patient becomes asymptomatic. Knowledge of these findings would be helpful when evaluating these patients for follow-up or for other reasons.


A survey of infective larvae of Gnathostoma in eels sold in Ho Chi Minh City.
To investigate the distribution of Gnathostoma spp in Ho Chi Minh City (HCM city), 1,081 eels were purchased from a local market twice a month from March 1998 to February 1999. Infective larvae of Gnathostoma spp detected from the flesh and liver of eels by the press preparation technique were examined and identified. Three hundred and fifty advanced third-stage larvae were recovered from liver, none from the flesh. The average rate of infection was 0.11; a high rate of infection was found from August to November and a low rate of infection from February to May. The average number of larvae/eel was 2.9; the greatest number of larvae/eel was in January whereas the lowest was in March and April. There was a marked decrease in both prevalence and intensity of infection from February to May, followed by a rise from June. The finding suggests that in HCM city, the infection rate abruptly decreases soon after the end of the rainy season and starts to rise when the rain comes and reaches its peak at the end of the rainy season. All recovered larvae were identified as G. spinigerum.


Using Small-Angle Scattering Techniques to Understand Mechanical Properties of Biopolymer-Based Biomaterials.
The design and engineering of innovative biopolymer-based biomaterials for a variety of biomedical applications should be based on the understanding of the relationship between their nanoscale structure and mechanical properties. Down the road, such understanding could be fundamental to tune the properties of engineered tissues, extracellular matrices for cell delivery and proliferation/differentiation, etc. In this tutorial review, we attempt to show in what way biomaterial structural data can help to understand the bulk material properties. We begin with some background on common types of biopolymers used in biomaterials research, discuss some typical mechanical testing techniques and then review how others in the field of biomaterials have utilized small-angle scattering for material characterization. Detailed examples are then used to show the full range of possible characterization techniques available for biopolymer-based biomaterials. Future developments in the area of material characterization by small-angle scattering will undoubtedly facilitate the use of structural data to control the kinetics of assembly and final properties of prospective biomaterials.


Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1.
Cancer-Associated Fibroblasts (CAFs) are the most prominent stromal cell type in breast tumors. CAFs promote tumor growth and metastasis by multiple mechanisms, including by mediating tumor-promoting inflammation. Immune modulation in the tumor microenvironment plays a central role in determining disease outcome. However, the functional interactions of CAFs with immune cells are largely unknown. Here we report a novel signaling axis between fibroblasts, cancer cells and immune cells in breast tumors that drives an immunosuppressive microenvironment, mediated by CAF-derived Chi3L1. We demonstrate that Chi3L1 is highly upregulated in CAFs isolated from mammary tumors and pulmonary metastases of transgenic mice, and in the stroma of human breast carcinomas. Genetic ablation of Chi3L1 in fibroblasts in vivo attenuated tumor growth, macrophage recruitment and reprogramming to an M2-like phenotype, enhanced tumor infiltration by CD8+ and CD4+ T cells and promoted a Th1 phenotype. These results indicate that CAF-derived Chi3L1 promotes tumor growth and shifts the balance of the immune milieu towards type 2 immunity. Taken together, our findings implicate fibroblast-derived Chi3L1 as a novel key player in the complex reciprocal interactions of stromal cells that facilitate tumor progression and metastasis, and suggest that targeting Chi3L1 may be clinically beneficial in breast cancer.


Attitudes of the Victorian oral health workforce to the employment and scope of practice of dental hygienists.
Increasing the number of dental hygienists and expanding their scope of practice are two policy directions that are currently being explored to increase the supply of dental services in the context of projected oral health workforce shortages in Australia. Understanding factors relating to the employment of hygienists and the attitudes of the oral health workforce to dental hygiene practice are important in this policy debate. A postal survey of a random sample of Victorian dentists, periodontists, orthodontists and hygienists was undertaken in 2006. Dentists and specialists were grouped into those whose practice employed or did not employ a hygienist. Data on the attitudes of dentists, specialists and hygienists towards various aspects of dental hygiene practice were explored. A response rate of 65.3 per cent was achieved. Hygienists believed that their employment made dental care more affordable (53.7 per cent) and improved access to dental care (88.1 per cent), while few dentists believed hygienists made care more affordable. Most hygienists believed they were capable of diagnosing periodontal disease and dental caries and formulating a treatment plan, but there was less support from employers and non-employers. Dentists were strongly opposed to independent practice for dental hygienists, although there was qualified support from employers for increasing the scope of practice for hygienists. Dentists who worked with hygienists acknowledged their contribution to increasing practice profitability, efficiency and accessibility of dental services to patients. Hygienists and employers supported increasing the scope of dental hygiene practice, however the majority of non-employers opposed any expansion.


Has there been a change in the end-of-life decision-making over the past 16 years?
Physicians' decision-making in end-of-life (EOL) care includes many medical, ethical and juridical aspects. We studied the changes of these decisions over time and factors influencing them. A postal survey including two hypothetical patient scenarios was sent to 1258 Finnish physicians in 2015 and to 1182 in 1999. The attitudes, values and background factors of the physicians were also enquired. The response rate was 56%. The physicians' decisions to choose palliative approaches over active or intensive care increased from 1999 to 2015 when a terminally ill prostate cancer patient had probable iatrogenic gastrointestinal bleeding (53% vs 59%, p=0.014) and waited to meet his son (46% vs 60%, p<0.001) or a minister (53% vs 71%, p<0.001). Training in EOL care independently increased palliative approaches. Patient's benefit (96% vs 99%, p=0.001), ethical values (83% vs 93%, p<0.001) and patient's (68% vs 86%, p<0.001) or physician's (44% vs 63%, p<0.001) legal protection were considered more influential to the decisions in 2015, while the family's benefit was regarded as less influential to the decisions than it was in 1999 (37% vs 25%, p<0.001). Physicians were more willing to give a hospice voucher for an advanced breast cancer patient in 2015 (34% vs 58%, p<0.001). Our findings may reflect the transition to a stronger emphasis on patient-centred care and a stronger tendency to avoid futile therapies that have only short-term goals. The results highlight that education in all aspects of EOL care should be incorporated into the post-graduate training of medical specialties that take care of dying patients.


Effect of silymarin on metabolic factors of food-restricted over conditioned Wistar rats.
This study was conducted to evaluate the changes in serum metabolic factors of over conditioned pregnant rats treated with silymarin in food restriction condition. Sixty pregnant Wistar rats were divided into five equal groups. All rats received high energy diet before treatments. Control group were fed ad libitum (Non-FR). Rats in other groups received 50% of the food intake of Non-FR group and served as food-restricted (FR) groups. Three of five FR groups received 150, 200 and 400 mg kg(-1) silymarin, respectively (FR-150, 200, 400). Another FR group (FR-Con) and the Non-FR group did not receive any silymarin. Glucose, triglyceride, LDL and HDL cholesterol, total cholesterol, thyroid hormones and cortisol were measured in serum. All factors were significantly different between groups except free-T4 and T4. Serum glucose concentrations in FR-150 and 200 and Non-FR groups were lower than FR-Con and FR-400. Silymarin significantly increased serum triglycerides, LDL cholesterol and cholesterol contents in FR groups. The highest levels of these factors were noted in 200 mg silymarin-treated group. HDL cholesterol was highest in FR-Con; meanwhile FR-200 group had the lowest HDL cholesterol. Serum cortisol decreased in treated and untreated FR groups except FR-150 group. Free-T3 and T3 concentrations in FR-400 and FR-Con groups were higher than the other silymarin treated groups. In conclusion our results indicate that 200 mg kg(-1) of silymarin in Wistar rats is the best dosage to achieve metabolic benefits. Silymarin has positive effects on lipid metabolism and can modulate serum triglyceride and cholesterol concentrations in food restriction condition. Also, the present findings suggest that silymarin under food restriction situation exerts a decreasing effect upon peripheral conversion of T4 to T3.


Vaginal natural oxygenation device (VNOD) for concomitant administration of hyaluronic acid and topical hyperbaric oxygen to treat vulvo-vaginal atrophy: a pilot study.
This is a pilot study to evaluate the effectiveness of concomitant administration of hyaluronic acid and topical hyperbaric oxygen therapy (THOT) by a specifically designed medical device (vaginal natural oxygenation device, VNOD) in improving the symptomatology of postmenopausal patients with vulvo-vaginal atrophy (VVA). Women with diagnosis of severe VVA from September 2017 to May 2018 were included. Five biweekly administration of THOT and concomitant of hyaluronic acid were performed with a specifically designed medical device. In each occasion, the intensity of patient's symptoms (well-being such as absence of dyspareunia, vaginal dryness, vulvar and/or vaginal itching; vaginal burning; presence of fluid) was determined with a graduated scale from 1 to 6 and the vaginal elasticity and the vaginal wall epithelium appearance were also determined with a graduated scale from 1 to 5. The change in all parameters from baseline to end of therapy was evaluated. Twenty-five patients were considered for the final analysis. A significant improvement in well-being (0.3 vs. 5.1, p < 0.001), vaginal burning (0.2 vs. 5.1, p < 0.001), presence of fluid (0.6 vs. 4.9, p < 0.001), vaginal epithelium appearance (1.8 vs. 4.7, p < 0.001), and vaginal elasticity (1.1 vs. 3.8, p < 0.001) was observed between the first and the last therapy session. All the patients reported a recovery of their sexuality at the end of the five treatment sessions. In this pilot study, the use of VNOD seems to be a valid treatment of VVA, resulting in a completely natural type of therapy well accepted by patients with immediate therapeutic effects and without side effects; these findings must be confirmed in a well-designed randomized controlled trial.


Spatiotemporal refinement of signal flow through association cortex during learning.
Association areas in neocortex encode novel stimulus-outcome relationships, but the principles of their engagement during task learning remain elusive. Using chronic wide-field calcium imaging, we reveal two phases of spatiotemporal refinement of layer 2/3 cortical activity in mice learning whisker-based texture discrimination in the dark. Even before mice reach learning threshold, association cortex-including rostro-lateral (RL), posteromedial (PM), and retrosplenial dorsal (RD) areas-is generally suppressed early during trials (between auditory start cue and whisker-texture touch). As learning proceeds, a spatiotemporal activation sequence builds up, spreading from auditory areas to RL immediately before texture touch (whereas PM and RD remain suppressed) and continuing into barrel cortex, which eventually efficiently discriminates between textures. Additional correlation analysis substantiates this diverging learning-related refinement within association cortex. Our results indicate that a pre-learning phase of general suppression in association cortex precedes a learning-related phase of task-specific signal flow enhancement.


Modern or traditional health care? Understanding the role of insurance in health-seeking behaviours among older Ghanaians.
This paper examined the association between wealth and health insurance status and the use of traditional medicine (TM) among older persons in Ghana. There have been considerable efforts by sub-Saharan African countries to improve access to primary health care services, partly through the implementation of risk-pooling community or national health insurance schemes. The use of TM, which is often not covered under these insurance schemes, remains common in many countries, including Ghana. Understanding how health insurance and wealth influence the use of TM, or otherwise, is essential to the development of equitable health care policies. The study used data from the first wave of the World Health Organisation's Study of Global Ageing and Adult Health conducted in Ghana in 2008. Descriptive statistics and negative loglog regression models were fitted to the data to examine the influence of insurance and wealth status on the use of TM, controlling for theoretically relevant factors. Seniors who had health insurance coverage were also 17% less likely to frequently seek treatment from a TM healer relative to the uninsured. For older persons in the poorest income quintile, the odds of frequently seeking treatment from TM increased by 61% when compared to those in the richest quintile. This figure was 46%, 62% and 40% for older persons in poorer, middle and richer income quintiles, respectively, compared to their counterparts in the richest income quintile. The findings indicate that TM was primarily used by the poor and persons who were not enrolled in the National Health Insurance Scheme. TM continues to be a vital health care resource for the poor and uninsured older adults in Ghana.


[Differences in influenza vaccination coverage among subgroups of adult immigrants residing in Italy at risk for complications (2012-2013)].
to evaluate differences in influenza vaccination coverage (IVC) in immigrants at risk for influenza-related complications, according to their area of origin and length of stay in Italy. cross-sectional survey conducted on the sample of foreign citizens included in the survey on health conditions and use of health services of the Italian resident population (Italian national institute of statistics, 2012-2013). analysis conducted on 885 foreign adult citizens (≥18 years) at risk for influenza-related complications (elderly residents ≥65 years and residents with specific chronic diseases). vaccination coverage ratios (VCR) comparison between long-term immigrants (≥10 years) and recent immigrants (<10 years), and between non-African and African immigrants, adjusted by demographic and socioeconomic characteristics and level of health services utilization. IVC among immigrants was 15.6%, significantly higher in long-term immigrants (18.3%) compared to recent immigrants (10.2%) (VCR: 1.79; 95%CI 1.21-2.66), and in non-African immigrants (17.1%) compared to African immigrants (9.4%) (VCR: 1.82; 95%CI 1.04-3.17). After adjusting on the basis of demographic and socioeconomic characteristics and for level of health services utilization between the compared subgroups, the difference in IVC according to the length of stay was greatly reduced (VCR: 1.41; 95%CI 0.94- 2.10), while IVC difference reduction according to area of origin was less relevant (VCR: 1.66; 95%CI 0.95-2.91). demographic and socioeconomic characteristics and level of health services utilization explained part of the difference in IVC between the compared subgroups, particularly between long-term and recent immigrants. The difference in IVC between African immigrants and immigrants from other areas remained quite pronounced even after adjusting on the basis of these factors. This suggests that IVC, especially in African immigrants, is affected by other informal barriers, such as cultural and linguistic barriers, that need to be addressed when planning effective immunization access strategies.


Catalytic consequences of open and closed grafted Al(III)-calix[4]arene complexes for hydride and oxo transfer reactions.
An approach for the control and understanding of supported molecular catalysts is demonstrated with the design and synthesis of open and closed variants of a grafted Lewis acid active site, consisting of Al(III)-calix[4]arene complexes on the surface of silica. The calixarene acts as a molecular template that enforces open and closed resting-state coordination geometries surrounding the metal active sites, due to its lower-rim substituents as well as site isolation by virtue of its steric bulk. These sites are characterized and used to elucidate mechanistic details and connectivity requirements for reactions involving hydride and oxo transfer. The consequence of controlling open versus closed configurations of the grafted Lewis acid site is demonstrated by the complete lack of observed activity of the closed site for Meerwein-Ponndorf-Verley (MPV) reduction; whereas, the open variant of this catalyst has an MPV reduction activity that is virtually identical to previously reported soluble molecular Al(III)-calix[4]arene catalysts. In contrast, for olefin epoxidation using tert-butyl-hydroperoxide as oxidant, the open and closed catalysts exhibit similar activity. This observation suggests that for olefin epoxidation catalysis using Lewis acids as catalyst and organic hydroperoxide as oxidant, covalent binding of the hydroperoxide is not required, and instead dative coordination to the Lewis acid center is sufficient for catalytic oxo transfer. This latter result is supported by density functional theory calculations of the transition state for olefin epoxidation catalysis, using molecular analogs of the open and closed catalysts.


Effect of noise tolerance on non-restorative sleep: a population-based study in Hong Kong.
The aim of this study was to assess the impact of auditory noise tolerance on non-restorative sleep using an objective audiometric test in a representative sample. A total of 202 Chinese individuals aged 15 years and above were recruited from a population-based household survey. Their non-restorative sleep was assessed by a single item, the degree of feeling refreshed on waking up, on a 0-10 scale, while noise tolerance was measured by the most comfortable level expressed in A-weighted decibels. The 202 individuals (106 women) had a mean degree of feeling refreshed on waking up of 6.5 on the 0-10 scale and a mean maximum comfortable sound level of 69.2 dB. A multivariable analysis showed that a 1 dB increase in noise tolerance was associated with a 0.1-unit increase in the degree of feeling refreshed after adjusting for age, education, marital status, occupation, exercise, smoking, alcohol consumption, household noise level, stress, anxiety and depression. Moreover, housewives, non-smokers and individuals who were less anxious or stressed felt significantly more refreshed on waking up. People with higher levels of noise tolerance experienced more refreshing sleep. Additional clinical consideration of enhancing noise tolerance in patients with sleep complaints is needed.


CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy.
Advances in immunotherapy have revolutionized care for some patients with cancer. However, current checkpoint inhibitors are associated with significant toxicity and yield poor responses for patients with central nervous system tumors, calling into question whether cancer immunotherapy can be applied to glioblastoma multiforme. We determined that targeting the CD200 activation receptors (CD200AR) of the CD200 checkpoint with a peptide inhibitor (CD200AR-L) overcomes tumor-induced immunosuppression. We have shown the clinical efficacy of the CD200AR-L in a trial in companion dogs with spontaneous high-grade glioma. Addition of the peptide to autologous tumor lysate vaccines significantly increased the median overall survival to 12.7 months relative to tumor lysate vaccines alone, 6.36 months. This study was developed to elucidate the mechanism of the CD200ARs and develop a humanized peptide inhibitor. We developed macrophage cell lines with each of four CD200ARs knocked out to determine their binding specificity and functional response. Using proteomics, we developed humanized CD200AR-L to explore their effects on cytokine/chemokine response, dendritic cell maturation and CMV pp65 antigen response in human CD14+ cells. GMP-grade peptide was further validated for activity. We demonstrated that the CD200AR-L specifically targets a CD200AR complex. Moreover, we developed and validated a humanized CD200AR-L for inducing chemokine response, stimulating immature dendritic cell differentiation and significantly enhanced an antigen-specific response, and determined that the use of the CD200AR-L downregulated the expression of CD200 inhibitory and PD-1 receptors. These results support consideration of a CD200AR-L as a novel platform for immunotherapy against multiple cancers including glioblastoma multiforme.


[Summary version of the Standards, Options and Recommendations for the use of recombinant erythropoietin (epoietin-alpha and beta, darbepoietin-alpha, EPO) in the management of anaemia in oncology - Update 2003].
The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. To update the Standards, Options and Recommendations clinical practice guidelines for the use of recombinant erythropoietin (epoietin alpha and beta darbepoietin-alpha, EPO) in the management of anaemia in oncology. To define, on the basis of the critical appraisal of the best available evidence and expert agreement, the clinical situations in which the administration of rHuEPO is indicated, and those in which it is not indicated, except in the setting of randomised controlled trial. The working group identified the questions requiring up-dating from the previous guideline. Medline and Embase were searched using specific search strategies from January 1999 to October 2002. Literature monitoring was performed to identify randomised clinical trials published between October 2002 to November 2003. In addition several Internet sites were searched in October 2002. A total of 36 new references, corresponding to 30 randomised clinical trials, were identified. The role of rHuEPO is certain when the haemoglobin concentration is below 10 g/dL, but remains uncertain when the concentration is between 10 g/dL and 12 g/dL. When the haemoglobin concentration is between 12 g/dL and 14 g/dL there is no justification to use rHuEPO to prevent anaemia, except in the setting of autologous blood transfusion programmes before major surgery. No anti-anaemic treatment is justified if the haemoglobin concentration is higher than 14 g/dL, except in the setting of a randomised clinical trial.


Use of boar spermatozoa for artificial insemination. III. Fecundity of boar spermatozoa stored in Beltsville liquid and Kiev extenders for three days at 18 C.
A field trial was conducted on several hundred farms in The Netherlands to compare the fertilizing capacity of boar spermatozoa stored for 1, 2, or 3 d at 18 C in either Kiev or Beltsville liquid extender (BL-1). Two storage volumes (25 and 100 ml) were used. Twelve Dutch Landrace boars, all in routine commercial artificial insemination service, provided the semen in twice-a-week collections. Over an 8-wk period in March and April, 1979, 2,849 sows and gilts were inseminated. Farrowing rates were higher (P less than .0001) with Kiev extender than with BL-1 extender (69.3 vs 60.5%) when semen was used over a 3 d period. The volume at which the semen was extended and stored had no effect on any parameter. Farrowing rate declined significantly when semen stored at 18 C for more than 2 d was used (74.5% vs 64.7% with semen stored for 1 and 3 in Kiev extender; 65.9% vs 52.7% with semen stored for 1 and 3 d in BL-1 extender). The farrowing rate, total number of pigs/litter and live pigs/litter were significantly higher for sows than for gilts inseminated with similar extended semen. On the basis of the results of this trial, Kiev extender appears to be more suitable as a diluent for liquid semen than does BL-1. AI with semen extended and stored for 3 d at 18 C can be expected to result in a lower farrowing rate than AI with semen stored for 1 or 2 d.


Parents Produce Explicit Cues That Help Toddlers Distinguish Joking and Pretending.
While separate pieces of research found parents offer toddlers cues to express that they are (1) joking and (2) pretending, and that toddlers and preschoolers understand intentions to (1) joke and (2) pretend, it is not yet clear whether parents and toddlers consider joking and pretending to be distinct concepts. This is important as distinguishing these two forms of non-literal acts could open a gateway to understanding the complexities of the non-literal world, as well as the complexities of intentions in general. Two studies found parents offer explicit cues to help 16- to 24-month-olds distinguish pretending and joking. Across an action play study (n = 25) and a verbal play study (n = 40) parents showed more disbelief and less belief through their actions and language when joking versus pretending. Similarly, toddlers showed less belief through their actions, and older toddlers showed less belief through their language. Toddlers' disbelief could be accounted for by their response to parents' language and actions. Thus, these studies reveal a mechanism by which toddlers learn to distinguish joking and pretending. Parents offer explicit cues to distinguish these intentions, and toddlers use these cues to guide their own behaviors, which in turn allows toddlers to distinguish these intentional contexts.


Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shares immunologic features with multiple sclerosis (MS). Because IM interferon beta-1a (IM IFNbeta-1a) is an effective and safe treatment for MS, we conducted a dose-ranging efficacy study of IFNbeta-1a in patients with CIDP. Adults with IV immunoglobulin (IVIg)-dependent CIDP (n = 67) were enrolled in this 32-week double-blind trial and randomized to IM IFNbeta-1a. Patients received 30 microg once weekly plus placebo (n = 12), IM IFNbeta-1a 60 microg once weekly plus placebo (n = 11), IM IFNbeta-1a 30 microg twice weekly (n = 11), IM IFNbeta-1a 60 microg twice weekly (n = 11), or placebo twice weekly (n = 22). Participants were maintained on IVIg through week 16, when IVIg was discontinued. Patients who worsened were restarted on IVIg. The primary outcome was total IVIg dose (g/kg) administered from week 16 to 32. There was no difference in total IVIg dose administered after week 16 for patients treated with IFNbeta-1a (1.20 g/kg) compared with placebo (1.34 g/kg; p = 0.75). However, exploratory analyses suggested IFNbeta-1a significantly reduced total dose of IVIg compared with placebo for participants who required either high-dose IVIg (>0.95 g/kg per month) or had greater weakness at baseline (Medical Research Council sum score <51). Adverse events included flu-like symptoms, headache, and fatigue in the IFNbeta-1a groups. Interferon beta-1a (IFNbeta-1a) therapy did not provide significant benefit over IV immunoglobulin (IVIg) therapy alone for patients with chronic inflammatory demyelinating polyradiculoneuropathy. However, IFNbeta-1a might be beneficial for patients with more severe disability or those needing high doses of IVIg. This study was designed to provide Class I evidence for the safety and efficacy of IM IFNbeta-1a in the treatment of CIDP but has been subsequently classified as Class II due to a >20% patient dropout rate. Thus, this randomized, controlled clinical trial provides Class II evidence of no effect on primary and secondary endpoints of 4 dosage regimens of IM IFNbeta-1a added to IVIg in persons with CIDP.


GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells.
Emerging evidence has revealed that miRNAs could upregulate the expression levels of target genes. However, the molecular mechanism underlying upregulation of targets mediated by miRNAs remains unclear. In this study, we found a novel miRNA named MIR-G-1 by GRSF1-RNA immunoprecipitation (RIP)-deep sequencing, which could directly target and upregulate LMNB1 and TMED5 in a GRSF1-dependent manner in cervical cancer cells. In addition, upregulated MIR-G-1 in cervical cancer promoted a malignant phenotype in vitro and in vivo. TMED5 could interact with WNT7B and thus activated the canonical WNT-CTNNB1/β-catenin signaling pathway. MIR-G-1 mediated the activation of this pathway. Furthermore, MIR-G-1 promoted serum starvation-induced nuclear macroautophagy/autophagy, and accelerated taxol (TAX)-induced DNA-damage repair in cervical cancer cells. Collectively, these findings may provide a new insight into the upregulation mechanism and nuclear autophagy mediated by miRNAs and provide a potential biomarker for cervical cancer. Abbreviations: 3'UTR: 3' untranslated region; EMSA: electrophoretic mobility shift assay; EMT: epithelial-mesenchymal transition; GRSF1: G-rich RNA sequence binding factor 1; IF: immunofluorescence; IP: immunoprecipitation; IHC: immunohistochemistry; lnc: long noncoding; miRNA:microRNA; TAX: taxol; TMED5: transmembrane p24 trafficking protein 5.